Optically active tetrahydroquinolines, particularly the ones having a substituent at position 2, namely optically active 2-substituted-1,2,3,4-tetrahydroquinolines, are contained in many natural bioactive compounds such as alkaloids and are important compounds widely used as pharmaceuticals.
For efficient production of optically active 2-substituted tetrahydroquinolines, various methods involving asymmetric reduction of the corresponding 2-substituted-quinolines to give optically active 2-substituted-1,2,3,4-tetrahydroquinolines in one step have been developed. For example, known methods include a method using Hantzsch ester as a reducing agent and a chiral acid as an asymmetric catalyst (Non Patent Literature 1); a method using hydrogen gas as a reducing agent and an iridium catalyst having a chiral ligand (Non Patent Literature 2 and 3); and a method using sodium formate as a reducing agent, water as a solvent and a rhodium catalyst coordinated with TsDPEN or its related ligand (Non Patent Literature 4).
However, these methods are not necessarily satisfactory for industrial use. For example, the method using Hantzsch ester as a reducing agent (Non Patent Literature 1) requires a stoichiometric amount of very expensive Hantzsch ester and thus is difficult to apply to industrial production. The method using hydrogen gas as a reducing agent (Non Patent Literature 2 and 3) requires high-pressure conditions (for example, 40 to 50 atmospheres) for a reaction with hydrogen due to the low conversion of quinoline, and thus needs specialized equipment for large scale production, which leads to high production cost.
The method using inexpensive sodium formate as a reducing agent and water as a solvent (Non Patent Literature 4) is also industrially disadvantageous because of the following reasons: most of quinoline compounds as a starting material are poorly water-soluble; precise pH adjustment is indispensable; and rhodium complexes essential as a catalyst are expensive. In addition, a reaction of 2-methylquinoline using an iridium catalyst having a TsDPEN ligand (Non Patent Literature 4) has problems including the low enantiomeric excess of the product, which is as low as 11%.
Under such circumstances, there is a pressing need to develop methods for providing optically active 2-substituted-1,2,3,4-tetrahydroquinolines usable as a unit of many useful substances in an industrially advantageous manner.